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Cortisol/Progesterone Antagonism in Regulation of 15-Hydroxysteroid Dehydrogenase Activity and mRNA Levels in Human Chorion and Placental Trophoblast Cells at Term

Canadian Institutes for Health Research Group in Fetal and Neonatal Health and Development, Departments of Physiology and Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario M5S 1A8, Canada

Address all correspondence and requests for reprints to: Falguni A. Patel, M.D., 1 Kings College Circle, Medical Sciences Building, Room 3344, Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada. E-mail: fal.patel{at}utoronto.ca

Abstract

PGs mediate parturition events. 15-Hydroxyprostaglandin dehydrogenase (PGDH) catalyzes the first step in the metabolism of PGs to render them inactive. We have reported previously that cortisol (F) decreases PGDH activity and progesterone (P₄) maintains PGDH in human chorion and placenta at term. To study the interaction of P₄ and F on the regulation of PGDH, we treated chorion and placental trophoblast cells in culture with combinations of F, dexamethasone, P₄, trilostane, and medroxyprogesterone acetate (MPA). Following a 24-h steroid treatment period and 4-h PGF₂ challenge, culture media and cells were collected for measurement of PGF₂ levels and PGDH mRNA by RIA and Northern blotting analysis. F and dexamethasone decreased PGDH activity and mRNA levels. Exogenous P₄ did not significantly alter PGDH activity or mRNA levels; however, MPA significantly stimulated PGDH activity. Trilostane decreased P₄ production by more than 90% and also decreased PGDH activity and expression. Coincubation with P₄ or MPA reversed trilostane inhibition of PGDH, consistent with a stimulatory role for endogenous P₄ on PGDH. MPA significantly reversed F inhibition of PGDH activity and mRNA levels. In the presence of trilostane, P₄ at equimolar concentration to F reversed F inhibition of PGDH mRNA levels. These findings suggest that F may be acting as an endogenous inhibitor of P₄ action in the regulation of PGDH at term.

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